RESUMEN

Clear cell carcinomas are rare and relatively chemo-insensitive ovarian cancers with a characteristic molecular pathogenesis. Alterations in ARID1A, a component of the multiprotein chromatin remodeling complex SWI/SNF, are likely early events in the development of ovarian clear cancers arising from atypical endometriosis. Insight into additional driver events and particularly mutations in the same chromatin remodeling complex is limited. Isolated loss of SMARCA4, encoding the ATPase of the SWI/SNF complex, characterizes other aggressive gynecologic cancers including small cell carcinomas of the ovary hypercalcemic type (SCCOHT), undifferentiated endometrial carcinomas (UDEC), and uterine sarcomas (SDUS). The ovarian clear cell carcinoma of a 48-year-old showed in the initial surgical specimen a subclonal loss of SMARCA4 in addition to an ARID1A mutation, i.e., two alterations in the SWI/SNF heterochromatin remodeling complex. We anticipated that the SMARCA4 loss would worsen the disease course in analogy to SCCOHT, UDEC, and SDUS. However, the disease did not accelerate. Instead, the recurrent disease showed restored SMARCA4 expression while retaining the ARID1A mutation. Combinatorial redundancy, diversity and sequence in the SWI/SNF complex assembly as well as DNA- and tissue-specificity may explain the observed irrelevance of SMARCA4 loss in the presented ARID1A mutated ovarian clear cell carcinoma.

RESUMEN

Kidney formation and nephrogenesis are controlled by precise spatiotemporal gene expression programs, which are coordinately regulated by cell-cycle, cell type-specific transcription factors and epigenetic/chromatin regulators. However, the roles of epigenetic/chromatin regulators in kidney development and disease remain poorly understood. In this study, we investigated the impact of deleting the chromatin remodeling factor Smarca4 (Brg1), a human Wilms tumor-associated gene, in Wnt4-expressing cells. Smarca4 deficiency led to severe tubular defects and a shortened medulla. Through unbiased single-cell RNA sequencing analyses, we identified multiple types of Wnt4 Cre-labeled interstitial cells, along with nephron-related cells. Smarca4 deficiency increased interstitial cells but markedly reduced tubular cells, resulting in cells with mixed identity and elevated expression of cell-cycle regulators and genes associated with extracellular matrix and epithelial-to-mesenchymal transition/fibrosis. We found that Smarca4 loss induced a significant upregulation of the oncogene Pttg1 and hyperproliferation of Wnt4 Cre-labeled cells. These changes in the cellular state could hinder the cellular transition into characteristic tubular structures, eventually leading to fibrosis. In conclusion, our findings shed light on novel cell types and genes associated with Wnt4 Cre-labeled cells and highlight the critical role of Smarca4 in regulating tubular cell differentiation and the expression of the cancer-causing gene Pttg1 in the kidney. These findings may provide valuable insights into potential therapeutic strategies for renal cell carcinoma resulting from SMARCA4 deficiency.

RESUMEN

ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, exhibits recurrent mutations in various types of human cancers, including liver cancer. However, the function of ARID1A in the pathogenesis of liver cancer remains controversial. Here, we demonstrate that Arid1a knockout may result in states of different cell differentiation, as indicated by single-cell RNA sequencing (scRNA-seq) analysis. Bulk RNA-seq also revealed that Arid1a deficiency upregulated these genes related to cell stemness and differentiation, but downregulated genes related to the hepatic functions. Furthermore, we confirmed that deficiency of Arid1a increased the expression of hepatic stem/progenitor cell markers, such as Cd133 and Epcam, and enhanced the self-renewal ability of cells. Mechanistic studies revealed that Arid1a loss remodeled the chromatin accessibility of some genes related to liver functions. Thus, Arid1a deficiency might contribute to cancer development by increasing the number of stem/progenitor-like cells through dysregulating the expression of these genes related to cell stemness, differentiation and liver functions.

Asunto(s)

Neoplasias Hepáticas , Proteínas Nucleares , Cromatina , Ensamble y Desensamble de Cromatina , Proteínas de Unión al ADN , Humanos , Células Madre , Factores de Transcripción

RESUMEN

The presence of sarcomatoid or rhabdoid features (which are associated with advanced disease and poor prognosis) is rarely observed in the subtypes of renal cell carcinoma (RCC). The SWI/SNF chromatin-remodeling complex, which is composed of evolutionarily conserved core subunits including SMARCB1/INI1 (SMARCB1), SMARCA4/BRG1 (SMARCA4), SMARCC1/BAF155 (SMARCC1), and SMARCC2/BAF170 (SMARCC2), can be regarded as the prototype of an epigenetic regulator of gene expression that is involved in tumor suppression. We analyzed the histological, immunohistochemical, and clinicopathological status in 72 cases of RCC with sarcomatoid or rhabdoid features, focusing on the expression status of the subunits of SWI/SNF chromatin-remodeling complex proteins. Cases with lost or reduced expression were defined as showing aberrant expression. The frequency of aberrant SMARCA4 immunoexpression of a sarcomatoid or rhabdoid component in clear cell RCC (ccRCC) (47/50, 94%) was significantly higher than that in non-ccRCC (4/9, 44%) (p < 0.001). In ccRCC without sarcomatoid or rhabdoid features, aberrant SMARCA4 immunoexpression was observed in 33 of 48 (67%) cases. Immunoreactivities for SMARCB1, SMARCA2, and SMARCC2 were retained in almost all subtypes of RCC. The patients with aberrant SMARCA4 expression in RCC with sarcomatoid or rhabdoid features achieved shorter progression-free survival compared with the patients with retained SMARCA4 expression (all subtypes of RCC, p = 0.0212; ccRCC, p = 0.0265). These results suggest that in ccRCC, aberrant SMARCA4 expression is one of the adverse prognostic factors or a high-grade malignant transforming factor. The evaluation of SMARCA4 immunoexpression may be a useful diagnostic tool to help distinguish ccRCC from non-ccRCC.

Asunto(s)

Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/química , Ensamble y Desensamble de Cromatina , ADN Helicasas/análisis , Neoplasias Renales/química , Proteínas Nucleares/análisis , Factores de Transcripción/análisis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Proteínas de Unión al ADN/análisis , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Nefrectomía , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Factores de Riesgo , Proteína SMARCB1/análisis , Factores de Tiempo

RESUMEN

Members of the human FET family of RNA-binding proteins, comprising FUS, EWSR1, and TAF15, are ubiquitously expressed and engage at several levels of gene regulation. Many sarcomas and leukemias are characterized by the expression of fusion oncogenes with FET genes as 5' partners and alternative transcription factor-coding genes as 3' partners. Here, we report that the N terminus of normal FET proteins and their oncogenic fusion counterparts interact with the SWI/SNF chromatin remodeling complex. In contrast to normal FET proteins, increased fractions of FET oncoproteins bind SWI/SNF, indicating a deregulated and enhanced interaction in cancer. Forced expression of FET oncogenes caused changes of global H3K27 trimethylation levels, accompanied by altered gene expression patterns suggesting a shift in the antagonistic balance between SWI/SNF and repressive polycomb group complexes. Thus, deregulation of SWI/SNF activity could provide a unifying pathogenic mechanism for the large group of tumors caused by FET fusion oncoproteins. These results may help to develop common strategies for therapy.

Asunto(s)

Ensamble y Desensamble de Cromatina/genética , Cromatina/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas de Unión al ARN/metabolismo , Línea Celular Tumoral , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Regulación de la Expresión Génica/genética , Humanos , Metilación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Oncogénicas/genética , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Proteínas de Unión al ARN/genética

RESUMEN

ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species. The vulnerability of ARID1A-deficient cancer cells results from low basal levels of GSH due to impaired expression of SLC7A11. The SLC7A11-encoded cystine transporter supplies cells with cysteine, a key source of GSH, and its expression is enhanced by ARID1A-mediated chromatin remodeling. Thus, ARID1A-deficient cancers are susceptible to synthetic lethal targeting of GCLC.

Asunto(s)

Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glutamato-Cisteína Ligasa/antagonistas & inhibidores , Glutatión/metabolismo , Proteínas Nucleares/deficiencia , Neoplasias Ováricas/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Quinuclidinas/farmacología , Factores de Transcripción/deficiencia , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Animales , Proteínas de Unión al ADN , Femenino , Glutamato-Cisteína Ligasa/metabolismo , Células HCT116 , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Terapia Molecular Dirigida , Proteínas Nucleares/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Factores de Transcripción/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.

Asunto(s)

Carcinoma Hepatocelular/genética , Proteínas de Unión al ADN/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Oncogenes/genética , Animales , Western Blotting , Carcinogénesis/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Metástasis de la Neoplasia , Proteínas Nucleares/metabolismo , Interferencia de ARN , Factores de Transcripción

RESUMEN

ARID1A, encoding the BAF250a subunit of SWI/SNF complex, has a high mutation frequency in numerous types of cancer. LncRNAs, a type of non-coding RNAs longer than 200 nucleotides, have been reported to interplay with SWI/SNF complex during cancer progression. However, whether the interaction between ARID1A and lncRNA affects hepatocellular carcinoma (HCC) still needs to be investigated. Here, we reveal that ARID1A interacts with lncRNA MVIH through some region(s) or domain(s) including ARID domain and C-terminal ARID1A protein binding domain. ARID1A upregulates its downstream target CDKN1A and suppresses HCC cell proliferation and migration through inhibiting MVIH. Our data suggests that deficiency or loss of functional mutations of ARID1A in HCC cells might contribute to the increased activity of certain cancer-promoting lncRNAs.

Asunto(s)

Carcinoma Hepatocelular/metabolismo , Movimiento Celular , Neoplasias Hepáticas/metabolismo , Proteínas Nucleares/metabolismo , ARN Largo no Codificante/metabolismo , Factores de Transcripción/metabolismo , Sitios de Unión , Carcinoma Hepatocelular/patología , Proliferación Celular , Proteínas de Unión al ADN , Genes Supresores de Tumor , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Unión Proteica

RESUMEN

The components of the Switch/Sucrose non-fermentable (SWI/SNF) complex are mutated in approximately 20% of human cancers. The A/T-rich interacting domain 1A (ARID1A) subunit has one of the highest mutation rates. Most notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas (OCCCs). We reported that inhibition of enhancer of zeste homology 2 (EZH2) is synthetically lethal in ARID1A-mutated OCCC.

RESUMEN

Biofilms are a source of therapeutic failures because of their intrinsic tolerance to antimicrobials. Candida glabrata is one of the pathogenic yeasts that is responsible for life-threatening disseminated infections and able to form biofilms on medical devices such as vascular and urinary catheters. Recent progresses in the functional genomics of C. glabrata have been applied to the study of biofilm formation, revealing the contribution of an array of genes to this process. In particular, the Yak1 kinase and the Swi/Snf chromatin remodeling complex have been shown to relieve the repression exerted by subtelomeric silencing on the expression of the EPA6 and EPA7 genes, thus allowing the encoded adhesins to exert their key roles in biofilm formation. This provides a framework to evaluate the contribution of other genes that have been genetically linked to biofilm development and, based on the function of their orthologs in Saccharomyces cerevisiae, appear to have roles in adaptation to nutrient deprivation, calcium signaling, cell wall remodeling and adherence. Future studies combining the use of in vitro and animal models of biofilm formation, omics approaches and forward or reverse genetics are needed to expand the current knowledge of C. glabrata biofilm formation and reveal the mechanisms underlying their antifungal tolerance.

Asunto(s)

Biopelículas/crecimiento & desarrollo , Candida glabrata/fisiología , Animales , Candida glabrata/genética , Candida glabrata/crecimiento & desarrollo , Candida glabrata/metabolismo , Candidiasis/microbiología , Candidiasis/patología , Adhesión Celular , Pared Celular/metabolismo , Biología Computacional/métodos , Modelos Animales de Enfermedad , Regulación Fúngica de la Expresión Génica , Genómica/métodos

RESUMEN

Germinal center (GC) reaction is crucial in adaptive immune responses. The formation of GC is coordinated by the expression of specific genes including Blimp-1 and Bcl-6. Although gene expression is critically influenced by the status of chromatin structure, little is known about the role of chromatin remodeling factors for regulation of GC formation. Here, we show that the SWI/SNF chromatin remodeling complex is required for GC reactions. Mice lacking Srg3/mBaf155, a core component of the SWI/SNF complex, showed impaired differentiation of GC B and follicular helper T cells in response to T cell-dependent antigen challenge. The SWI/SNF complex regulates chromatin structure at the Blimp-1 locus and represses its expression by interacting cooperatively with Bcl-6 and corepressors. The defect in GC reactions in mice lacking Srg3 was due to the derepression of Blimp-1 as supported by genetic studies with Blimp-1-ablated mice. Hence, our study identifies the SWI/SNF complex as a key mediator in GC reactions by modulating Bcl-6-dependent Blimp-1 repression.

Asunto(s)

Proteínas Cromosómicas no Histona/fisiología , Regulación de la Expresión Génica/fisiología , Centro Germinal/fisiología , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Animales , Diferenciación Celular , Cromatina/química , Ratones , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Conformación Proteica

RESUMEN

The PBAF subtype of the mammalian chromatin remodeling SWI/SNF complex has wide and diverse functions in transcription regulation and development, being both transcription activator and repressor. However, a mechanism accounting for such functional diversity remains unclear. Human PHF10/BAF45a subunit of the PBAF complex plays an important role in brain development but has not been studied sufficiently. We have shown that the PHF10 gene encodes 2 types of evolutionarily conserved, ubiquitously expressed isoforms that are incorporated into the PBAF complex in a mutually exclusive manner. One isoform contains C-terminal tandem PHD fingers, which in the other isoform are replaced by the consensus sequence for phosphorylation-dependent SUMO 1 conjugation (PDSM). PBAF complexes containing different PHF10 isoforms can bind to the promoters of the same genes but produce different effects on the recruitment of Pol II to the promoter and on the level of gene transcription. In addition, it is only the PBAF with PHD-containing isoform that activates proliferation. Our study demonstrates the existence of functionally different PBAF complexes in mammalian cell. It also provides an insight into the molecular structure and role of human PHF10/BAF45a and characterizes it as an essential PBAF subunit.

Asunto(s)

Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas de Neoplasias/metabolismo , Factores de Transcripción/metabolismo , Animales , Proliferación Celular , ADN Polimerasa II/genética , ADN Polimerasa II/metabolismo , Células HEK293 , Proteínas de Homeodominio/genética , Humanos , Proteínas de Neoplasias/genética , Fosforilación , Regiones Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína SUMO-1/metabolismo , Transcripción Genética